DESCRIPTION: (Verbatim from the Applicant's Abstract) Rett Syndrome (RTT) is a neurological disorder of early childhood onset that is characterized by developmental regression with loss of speech an of purposeful hand use, microcephaly and seizures. Usually sporadic, RTT is a common cause of profound mental retardation, affecting 1 in 10-15,000 females. Studies of rare familial cases, including a severely affected male, provide overwhelming evidence that RTT is due to de novo occurrence of X-linked dominant mutations of a gene that is subject to X-inactivation. Polymorphic marker typing of familial cases allowed exclusion of most regions of the X chromosome and focused the search for the RTT gene on band Xq28. Additional RTT families will be identified and studied to further delineate the candidate region. The proposed research will use a systematic approach and novel technologies to identify the gene responsible for this disorder and to determine its normal function in the nervous system; to discover the mutational mechanisms and to determine the consequences of the mutations for neuronal development or survival. The hypothesis that RTT is due to microdeletions in Xq28 will be tested by a systematic deletion search using sequence-tagged-sites PCR and pulsed-field-gel electrophoresis analyses with probes covering the Xq28 region. The hypothesis tat a genomic rearrangement causes two de novo mutations in Xq28 in a female with RTT and Incontinentia Pigmenti (IP), another X-linked dominant disorder lethal in males, will be tested by genomic approaches and by fluorescence in situ hybridization. The hypothesis that RTT mutations lead to differential gene expression will be evaluated by suppression subtractive hybridization methods and by comparative hybridization of cDNA from RTT-gene containing cell lines and matched controls to Gene Expression Microarrays. Candidate genes identified by any of the above approaches that map to Xq28 will be tested for mutation in unrelated RTT individuals. Differential expression patterns of genes located elsewhere in the genome may reveal pathways that are influenced by the RTT gene's function. In addition, human gene mapping and sequencing databases contain numerous genes in the candidate region. Nineteen of them have been prioritized for mutation analysis. Once the RTT gene has been identified, Molecular diagnosis will become possible at early stages of the disorder. Newborn screening programs could identify presymptomatic mutation carriers. One the causative genetic mechanism is known, understanding of the pathophysiology may lead to early therapeutic intervention.